Hypoxic enlarged mitochondria protect cancer cells from apoptotic stimuli

• DOI: 10.1002/jcp.21984
• Publication Date: 2009-12-02T16:36:40Z
• Authors: Johanna Chiche; Matthieu Rouleau; Pierre Gounon; M. Christiane Bra...; Jacques Pouysségur; Nathalie M. Mazure
• Keywords: 0301 basic medicine; MESH: Cell Hypoxia; Apoptosis; Mitochondrial Membrane Transport Proteins; MESH: Membrane Transport Proteins; GTP Phosphohydrolases; Adenosine Triphosphate; MESH: Membrane Potential, Mitochondrial; Neoplasms; MESH: Adenosine Triphosphate; MESH: Neoplasms; [SDV.BDD]Life Sciences [q-bio]/Development Biology; MESH: Etoposide; Etoposide; Membrane Potential, Mitochondrial; MESH: Mitochondrial Proteins; MESH: Drug Resistance, Neoplasm; Cell Hypoxia; Mitochondria; 3. Good health; Phenotype; MESH: Membrane Proteins; MESH: GTP Phosphohydrolases; MESH: Mitochondria; MESH: Antineoplastic Agents, Phytogenic; MESH: RNA Interference; MESH: Phenotype; MESH: Hypoxia-Inducible Factor 1, alpha Subunit; Mitochondrial Proteins; 03 medical and health sciences; MESH: Cell Proliferation; Humans; MESH: Tumor Suppressor Proteins; Cell Proliferation; MESH: Humans; MESH: Apoptosis; MESH: Transfection; MESH: Time Factors; Membrane Proteins; Membrane Transport Proteins; Hypoxia-Inducible Factor 1, alpha Subunit; Antineoplastic Agents, Phytogenic; MESH: Proto-Oncogene Proteins; MESH: Hela Cells; Drug Resistance, Neoplasm; MESH: Staurosporine; MESH: Mitochondrial Swelling; Mitochondrial Swelling; HeLa Cells

AbstractIt is well established that cells exposed to the limiting oxygen microenvironment (hypoxia) of tumors acquire resistance to chemotherapy, through mechanisms not fully understood. We noted that a large number of cell lines showed protection from apoptotic stimuli, staurosporine, or etoposide, when exposed to long‐term hypoxia (72 h). In addition, these cells had unusual enlarged mitochondria that were induced in a HIF‐1‐dependent manner. Enlarged mitochondria were functional as they conserved their transmembrane potential and ATP production. Here we reveal that mitochondria of hypoxia‐induced chemotherapy‐resistant cells undergo a HIF‐1‐dependent and mitofusin‐1‐mediated change in morphology from a tubular network to an enlarged phenotype. An imbalance in mitochondrial fusion/fission occurs since silencing of not only the mitochondrial fusion protein mitofusin 1 but also BNIP3 and BNIP3L, two mitochondrial HIF‐targeted genes, reestablished a tubular morphology. Hypoxic cells were insensitive to staurosporine‐ and etoposide‐induced cell death, but the silencing of mitofusin, BNIP3, and BNIP3L restored sensitivity. Our results demonstrate that some cancer cells have developed yet another way to evade apoptosis in hypoxia, by inducing mitochondrial fusion and targeting BNIP3 and BNIP3L to mitochondrial membranes, thereby giving these cells a selective growth advantage. J. Cell. Physiol. 222: 648–657, 2010. © 2009 Wiley‐Liss, Inc.